Retinopathy of Prematurity –Promising Newer Modalities of Treatment. Indian Pediatrics, VOLUME 49_FEBRUARY 16, 2012

1. R E V I E W ARTICLE
Retinopathy of Prematurity –Promising Newer Modalities of Treatment
HS NIRANJAN, NAVEEN BENAKAPPA, KR BHARATH KUMAR REDDY, SHIVANANDA AND M VASUDEVA KAMATH
From the Division of Neonatology, Indira Gandhi Institute of Child Health, Bangalore, Karnataka.
Correspondence to: Dr HS Niranjan, No. 505, 54th cross, 3rd Block, Rajajinagar, Bangalore 560 010, Karnataka, India.
drniranjan_hs@yahoo.com
Retinopathy of prematurity (ROP) is a disorder of neonatal retinal vascularization. The incidence is increasing in
developing countries like India in view of the rising numbers of preterm deliveries and improved neonatal care. Traditional
modalities of treatment included cryotherapy and laser therapy, which were laborious and required special training.
Hence, research is on way to find novel treatment modalities directed at various levels of pathogenesis for this blinding
disease. We reviewed the published and unpublished literature on newer methods of ROP management. The
pathogenesis of ROP has been studied with respect to the mediators of angiogenesis. Anti vascular endothelial growth
factor (Anti-VEGF) therapy has been extensively studied and the studies have demonstrated its promising role early
stages of ROP. The role of Insulin like growth factor (IGF), Granulocyte colony stimulating factor (GCSF), and June
kinases (JNK) inhibitors are being studied by various researchers across the world. Gene therapy holds promise in the
reversal of ROP changes.
Key words: Anti-VEGF, IGF, GSCF, Gene therapy, JNK1 inhibitor, Retinopathy.
R
etinopathy of prematurity (ROP) is a Complications are post-operative pain, lid edema,
developmental disorder that occurs in the laceration and hemorrhage of conjunctiva, preretinal and
incompletely vascularized retina of premature vitreous hemorrhage. Laser (light amplification by
infants and is an important cause of blindness stimulated emission of radiation) therapy evolved as the
in children in both the developed and the developing primary modality of treatment in 1990’s, with lesser
countries. Progress in neonatal intensive care in recent complications, and provided blindness prevention as
years has led to an increased survival of extremely low effectively as cryotherapy. However, the total cost of
birth weight (ELBW) infants weighing ≥1000 g at birth required equipment for laser therapy was much higher
and, subsequently, to an increasing incidence of ROP [1]. than for cryotherapy. This factor may have to be
Lack of a screening program in India has led to larger considered for the developing countries of the world,
number of babies developing retinal detachment, because where the incidence of ROP is on the rise. The
the retina in ROP eyes does not seem to grow with the complications reported with laser are burns of the cornea,
growing eyeball [2]. It gives way at a vulnerable point iris and lens, hyphema, retinal hemorrhages and
because it is stretched thin causing recurrent retinal choroidal rupture [6]. Hence, the need for newer
detachment [3]. Re-attachment of retina also does not modalities of treatment, which require less skill and
contribute to improved vision in these infants. equipment. Some of these novel modalities are discussed
here.
Cryotherapy emerged as the standard treatment for
acute phase ROP in the 1980’s, following publication of VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF)
the results of Cryotherapy for Retinopathy of Prematurity
Cooperative Group (CRYO ROPCG) trial [4]. The study Two theories exist on the pathogenesis of ROP. The
showed significant decline in the progression of threshold mesenchymal spindle cells, exposed to hyperoxic extra
ROP at which stage the risk of blindness if untreated was uterine conditions, develop gap junctions. These gap
50%. Cryotherapy also significantly reduced the junctions interfere with the normal vascular formation,
unfavorable structural outcome of threshold ROP to triggering a neovascular response, as reported by Kretzer
49.3% at 3 months and 45.8% at 12 months [5]. and Hittner [7]. Ashton theorized that 2 phases exist [8].
Cryotherapy requires a general anaesthetic or sedation The first phase is at the time of premature birth, the infant
and ventilation. Conjunctival dissection is needed in retina becomes hyperoxic (even in room air) with
posterior disease to enable access for the cryoprobe. decreased levels of VEGF. For a period of time, vessel
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2. NIRANJAN, et al. NEWER TREATMENTS FOR RETINOPATHY OF PREMATURITY
formation is halted at the interface between the vascular greatly reduced in stage 5 [18]. In contrast, another study
and avascular retina (Phase I, clinically 22–30 weeks investigated 38 cases of stage 5 ROP at the time of
postmenstrual age). As the eye grows, the avascular retina vitrectomy and found increased VEGF immunoreactivity
continues to increase in size without accompanying inner in the vascularised regions of fibrovascular membranes
retinal vessels. This creates a peripheral area of hypoxic [19].Thus the role of vascular endothelial growth factor
retina, resulting in increased levels of VEGF, which (VEGF) in neovascularization and vascular permeability
stimulates angiogenesis (pathological neovasculari- of ROP is established [20]. Hence, therapy for ROP is
sation) at the interface between the vascular and directed at treating the underlying pathogenesis by
avascular retina (Phase II, clinically 31-45 weeks decreasing VEGF levels (specifically VEGF-A), either
postmenstrual age). This two phase process leads to by completely ablating the peripheral avascular retina
vision-threatening ROP most frequently in extremely that produces the VEGF (LASER therapy) or by
immature infants with other comorbidities of prematurity inactivating VEGF by binding it after its production (anti-
(risk factors for ROP). These new vascular channels are VEGF therapy).
not mature and do not respond to proper regulation.
Although many causative factors, such as low birth Bevacizumab, a humanized recombinant antibody,
weight, prematurity, and supplemental oxygen therapy that inhibits the biological activity of VEGF, has been
are associated with ROP, several indirect lines of widely used as a off-label treatment for ocular
evidence suggest the role of a genetic component in the angiogenesis disorders, including age-related macular
pathogenesis of ROP [9]. Genetic polymorphism may degeneration [21], proliferative diabetic retinopathy
alter the function of the genes that normally control (PDR) [22] and neovascular glaucoma [23]. It is a
retinal vascularization, such as VEGF, which may also be complete antibody rather than an antibody fragment like
involved in the pathogenesis of ROP. ranibizumab.
Anti-Vascular Endothelial Growth factor Therapy The BEAT–ROP study (Bevacizumab eliminates the
angiogenic threat of ROP) is a Phase II study (intravitreal
Vascular endothelial growth factor A (VEGF-A) is a
bevacizumab injections versus conventional LASER
known promoter of angiogenesis and is upregulated by
surgery for ROP). In one study, after injection of
hypoxia. It interacts with endothelial cells via its two
bevacizumab as the initial treatment, reduced
membrane-bound receptors, VEGFR-1 and VEGFR-2,
neovascular activity was seen on fluorescein angiography
which belong to the tyrosine kinase receptor family [10].
in 14 of 15 eyes under study. In three eyes, a tractional
VEGFR-1 controls the assembly of tubes and functional
retinal detachment developed or progressed after
vessels by endothelial cells. VEGFR-2 promotes the
bevacizumab injection. No other ocular or systemic
differentiation and proliferation of endothelial cells. Its
adverse effects were identified [24]. Bevacizumab has
expression is increased by hypoxia and potentiated by
been shown in a small case series to temporarily slow
VEGF [11,12]. An association with ischemia-induced
vasculogenesis and permanently halt angiogenesis,
proliferative diseases has clearly been established [13].
usually with a single intravitreal injection, when used for
VEGF-A plasma levels of infants born at term were
vision-threatening ROP stage 3 (acute phase ROP
reported to vary from 200 to 450 pg/mL during the first
including AP–ROP) [25].
few weeks of life and decline rapidly to adult range levels
of 10-110 pg/mL within a few months after birth [14]. Bevacizumab, given to extremely immature infants
Interestingly, plasma VEGF-A levels in preterm infants by intravitreous injection as low dose monotherapy
were found to be relatively low and stable during the first (0.625 mg in 0.025 mL of solution) or upto 0.75 mg, has
7 days of life (48 pg/mL, SD 6) [15]. Similarly, in a mouse not shown systemic or local toxicity. The most likely local
model of ischemia induced retinal revascularisation, complications of the injections are infectious and
immunohistochemistry for VEGFR-1 and VEGFR-2 traumatic. Infections can be avoided by strict sterile
revealed that the immunoreactivity of VEGFR-2 was technique followed by one week of appropriate antibiotic
increased in the vessels near the avascular area, whereas ophthalmic drops. Trauma may occur to the lens because
the pattern of VEGFR-1 expression in the hypoxic retina the injection is given too anteriorly. No systemic
was almost the same as that of control animals [16]. complications have been encountered to date whether
VEGFR-2 expression was found to be mainly associated bevacizumab given alone, or in combination with
with pathological neovascularisation and less with LASER surgery (when the retinal barrier has been
physiological postnatal vessel development [17]. One breached).
study found VEGF-A to be elevated in the subretinal fluid
in ROP stage 4 (mean 44.16 ng/mL, SD 18.72) and Thus, bevacizumab alone for ROP stage 3 may
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3. NIRANJAN, et al. NEWER TREATMENTS FOR RETINOPATHY OF PREMATURITY
become not just an adjunct to laser therapy or vitrectomy, pharmacokinetics and dosing of intravenous insulin-like
but primary treatment replacing laser therapy as standard growth factor-I and IGF-binding protein-3 complex in
of care, if efficacy and safety are validated by evidence- preterm infants. The recombinant human IGF-I (rhIGF-I/
based data. Laser eventually may be contraindicated rhIGFBP-3) equimolar proportion was effective in
because it is a very destructive therapy that is never increasing serum IGF-I levels and administration under
completely without residual effects and targets the same study conditions was safe and well tolerated. IGFBP-3 is
pathogenic substance: VEGF. ROP stages 4 and 5 will a protein that binds to IGF-I and regulates the availability
continue to occur due to late diagnosis of acute disease and activity of IGF-1. Mecasermin rinfabate mimics the
from less than adequately screened nurseries and in these effects of this natural protein complex (IGF-1/IGFBP-3)
desperate cases vitrectomy will be required, perhaps with in the bloodstream and is able to stay in the body for a
bevacizumab as an adjunctive therapy. longer period. The drug is under study and no studies to
prove its efficacy have been published yet. The cost
This novel drug therapy is being tried by many efficacy of this drug is quite disappointing when
neonatologists in developing countries where facilities compared to the other modalities.
for laser or cryotherapy may not be available. Moreover,
bevacizumab is a relatively easy and inexpensive GRANULOCYTE COLONY–STIMULATING FACTOR
treatment. In developing countries like India, where the
Granulocyte colony-stimulating factor (GCSF), a
per capita GDP is USD 543 (March 2006), the majority
biologic at commonly used to increase leukocyte counts
of patients cannot afford to pay USD 730 for a single vial
in neutropenic adults and children might also have a
of bevacizumab [26]. Therefore, efforts were made to
regulatory effect on vasculogenesis and thus prevent
make 20 fractions of 0.2 mL from a single vial, thus
ROP. GCSF has been shown to increase levels of insulin-
decreasing the cost to USD 38 per injection [27].
like growth factor-1(IGF-1), which supports the normal,
Another Anti-VEGF drug researched is Pegaptanib measured, calm vascularisation of the retina. Conversely,
sodium. The initial experience using pegaptanib sodium falling levels of IGF-1 appear to set off a disorderly,
to treat ROP suggest that the medication is well tolerated, aggressive vascularisation of the retina. In mouse
and helps to quieten the vascular activity in eyes with oxygen-induced retinopathy model, G-CSF significantly
severe posterior disease, but does not prevent the reduced vascular obliteration (P <0.01) and neovascular
development of retinal detachment. This thus is still tuft formation (P <0.01). G-CSF treatment also clearly
under study as an alternate anti VEGF therapy. We would rescued the functional and morphologic deterioration of
advocate caution; however, before introducing this new, the neural retina [34]. So GCSF, which is given to many
potentially exciting therapy, especially since large premature infants, might be used to prevent ROP,
randomized clinical trials are still to be conducted [28]. particularly in infants with falling IGF-1 levels. The
beauty of this approach, as opposed to, say, using
INSULIN LIKE GROWTH FACTOR – I bevacizumab, is that it doesn’t destroy VEGF. This hunch
led to a retrospective chart review of 213 infants who, for
It was shown that lack of insulin-like growth factor I non ophthalmic reasons, received GCSF in the neonatal
(IGF-I) in knockout mice prevents normal retinal intensive care unit at the University of Louisville. Fifty
vascular growth, despite the presence of vascular infants with low birth weight and a gestation of 32 weeks
endothelial growth factor, important to vessel and under were matched to a control group that did not
development [29]. Results from studies in premature receive GCSF. Only 10% of the infants who received
infants suggest that if the IGF-I level is sufficient after GCSF required laser treatment, compared with 18.6% of
birth, normal vessel development occurs and retinopathy the controls. Further, those babies in the GCSF group
of prematurity does not develop [30]. When IGF-I is who required laser had an exceptionally low average birth
persistently low, vessels cease to grow, maturing weight and had received relatively low doses of GCSF
avascular retina becomes hypoxic and vascular [35].
endothelial growth factor accumulates in the vitreous. As
IGF-I increase to a critical level, retinal neovasculari- Filgrastim is a human granulocyte colony-stimulating
zation is triggered [31]. These data indicate that serum factor (G-CSF)‚ produced by recombinant DNA
IGF-I levels in premature infants can predict which technology. It’s potential role in the prevention of ROP is
infants will develop retinopathy of prematurity and now being studied, hence the dose required and side
further suggests that early restoration of IGF-I in effects are still not documented. As this drug is more
premature infants to normal levels could prevent this easily available in India with costs ranging from 2500 –
disease [32]. A study from Sweden [33] studied the 3000 INR for a 300 mcg/mL vial, this would be a
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4. NIRANJAN, et al. NEWER TREATMENTS FOR RETINOPATHY OF PREMATURITY
beneficial adjunct to the treatment of ROP in a adenovirus offered the best efficiency in expression in
developing country like ours. retinal blood vessels compared with all the other vectors.
Moreover, the adenovirus expression was specific to the
JUN KINASES (JNK) INHIBITORS blood vessels of the inner retina and did not appear to be
expressed in the deeper neural retina. Hence, gene
The Jun kinases (JNK) belong to the mitogen-activated
therapy has a definite future in this blinding eye disease.
protein kinase (MAPK) family [36]. These kinases, which
are encoded by three separate loci, Jnk1-3, regulate key Funding: None; Competing interests: None stated.
cellular processes such as cell proliferation, migration,
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